Inhibition of the Multidrug Resistance P-Glycoprotein: Time for a Change of Strategy?

Callaghan, Richard; Luk, Frederick; Bebawy, Mary

doi:10.1124/dmd.113.056176

Cited by 365 publications

(258 citation statements)

References 149 publications

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“…There are several effectors of MDR, although the most common is upregulation of drug transporters such as ABCB1 (41). MDR has also been associated with E-cadherin loss (42,43).…”

Section: Discussionmentioning

confidence: 99%

miR-106b~25 cluster regulates multidrug resistance in an ABC transporter-independent manner via downregulation of EP300

Asaduzzaman

et al. 2015

Oncology Reports

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Abstract. MicroRNA (miR)-106b~25 cluster regulates bypass of doxorubicin and γ-radiation induced senescence by downregulation of the E-cadherin transcriptional activator EP300. We asked whether upregulation of miR-106~25 cluster generates cells with a truly multidrug resistant (MDR) phenotype and whether this is due to upregulation of the ATP-binding cassette (ABC) transporter P-glycoprotein. We used minimally transformed mammary epithelial breast cancer cells (MTMECs) in which the miR-106b~25 cluster was experimentally upregulated by lentiviral transfection or in which hairpins targeting either EP300 or E-cadherin mRNAs have been expressed with lentiviruses. We find that overexpression of miR-106b~25 cluster led to the generation of MDR MTMECs (resistant to etoposide, colchicine and paclitaxel). Paclitaxel resistance was also studied after experimental downregulation of EP300 or E-cadherin. However none of these cells overexpressed P-glycoprotein or where able to efflux a fluorescent derivative of paclitaxel, making this phenotype drug-transporter independent. Paclitaxel treatment in MTMECs led to an increase in early apoptotic cells (Annexin V-positive), activation of caspase-9 and increase in the proportion of cells at the G2/M phase of the cell cycle. However, MTMEC overexpressing miR-106b~25 cluster, or with EP300 or E-cadherin downregulated, showed less activation of apoptosis, caspase-9 and caspase-3/-7 activities. Thus, miR-106b~25 cluster controls transporter-independent MDR by apoptosis evasion via downregulation of EP300.

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“…There are several effectors of MDR, although the most common is upregulation of drug transporters such as ABCB1 (41). MDR has also been associated with E-cadherin loss (42,43).…”

Section: Discussionmentioning

confidence: 99%

miR-106b~25 cluster regulates multidrug resistance in an ABC transporter-independent manner via downregulation of EP300

Asaduzzaman

et al. 2015

Oncology Reports

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“…Međutim, u kliničkim ispitivanjima ovi lekovi se za sada nisu pokazali kao uspešni [14,15]. Stoga je, paralelno sa istraživanjem alternativnih pristupa prevazilaženju rezistencije [16], u okviru dizajna _____________________________ 1 Od engleskog ATP-binding cassette (ABC).…”

Section: Uvodunclassified

Computational models for predicting drug transport mediated by P-glycoprotein

Erić¹,

Kalinić²

2015

Arh farmaciju

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Kratak sadržajP-glikoprotein (Pgp) je transmembranski transporter koji, transportujući strukturno raznovrsne lekove iz unutrašnjosti ćelije u ekstracelularnu sredinu, može uticati na resorpciju, distribuciju i efikasnost većeg broja lekova. Prekomerna ekspresija Pgp-a u ćelijama predstavlja jedan od mehanizama razvoja rezistencije na lekove. Iz ovih razloga, potrebno je u ranoj fazi otkrića leka predvideti da li je potencijalni lek supstrat za Pgp, idealno i pre same sinteze. U tu svrhu, tokom poslednje decenije razvijen je veliki broj računarskih modela koji omogućavaju predviđanje transporta posredstvom Pgp-a samo na osnovu hemijske strukture. U ovom radu prikazan je pregled različitih pristupa koji su korišćeni u razvoju modela, razmotrene su njihove prednosti i nedostaci, kao i faktori koji u najvećoj meri utiču na pouzdanost predviđanja. Polispecifičnost ovog transportera predstavlja značajan izazov za većinu metoda računarske hemije. Ipak, dostignut nivo tačnosti modela koji su prikazani u litearaturi ukazuje na činjenicu da oni mogu doprineti racionalizaciji procesa dizajniranja novih lekova. Šira dostupnost eksperimentalnih podataka, kao i kombinovanje različitih pristupa modelovanju transporta, mogu dodatno unaprediti postojeće modele.Ključne reči: P-glikoprotein, računarski modeli, rezistencija, dizajn lekova.

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“…Combination therapy is believed to reduce the development of drug resistance when compared with treatment with one drug alone (40,41). It is therefore possible that itraconazole can prevent the resistance associated with monotherapy when combined with other medications.…”

Section: Itraconazole and Drug Resistancementioning

confidence: 99%

Repurposing itraconazole for the treatment of cancer

et al. 2017

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Abstract. The repurposing of drugs is becoming increasingly attractive as it avoids the lengthy process and cost implications associated with bringing a novel drug to market. Itraconazole is a broad-spectrum anti-fungal agent. An emerging body of in vivo, in vitro and clinical evidence have confirmed that it also possesses antineoplastic activities and has a synergistic action when combined with other chemotherapeutic agents. It acts via several mechanisms to prevent tumour growth, including inhibition of the Hedgehog pathway, prevention of angiogenesis, decreased endothelial cell proliferation, cell cycle arrest and induction of auto-phagocytosis. These allow itraconazole, either alone or in combination with other cytotoxic agents, to increase drug efficacy and overcome drug resistance. This study reviews the reported literature on the use of itraconazole in a variety of malignancies and highlights the recent insights into the critical pathways acted upon to prevent tumour growth.

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Inhibition of the Multidrug Resistance P-Glycoprotein: Time for a Change of Strategy?

Cited by 365 publications

References 149 publications

miR-106b~25 cluster regulates multidrug resistance in an ABC transporter-independent manner via downregulation of EP300

miR-106b~25 cluster regulates multidrug resistance in an ABC transporter-independent manner via downregulation of EP300

Computational models for predicting drug transport mediated by P-glycoprotein

Repurposing itraconazole for the treatment of cancer

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